The goal of this project is to develop new compounds of value in the study and treatment of AIDS. The approach is to synthesize oligonucleotide analogues that will penetrate cell membranes, survive attack by nucleases, and selectively inhibit HIV replication. Special attention will be given to cholesteryl conjugated derivatives and related compounds in long term cell culture systems, and subsequent efforts will be devoted to developing a practical procedure for large scale synthesis of these compounds for eventual testing in animals. New oligonucleotide analogues with potential as inhibitors of HIV will be synthesized and tested for recognition of specific RNA sequences, as inhibitors of protein synthesis in a cell free system, and as inhibitors of HIV in cell culture (short and long term). Compounds to be examined include oligonucleotide phosphoramidates (0=PNH2) and analogues with mixed cationic, methyl sulfoxide, phosphorothioate, phosphodiester, alkyl phosphotriester, phosphoramidate, and methyl phosphonate backbones.